During this period, the project team has further characterized the previously developed lead molecules of interest, and shown that inhibition of PIP4K by a small molecule inhibitor or silencing leads to change in the equilibrium of phosphatidyl ionosotides that increases autophagy and reduces mutant huntington protein in human patient fibroblasts and aggregates in neurons. In a Huntington Drosophila model silencing the gene for PIP4K leads to a recovery of motor performance and retinal degeneration, caused by the mutant huntington protein. This suggests that PIP4K is a novel pharmacological target for neurodegenerative diseases such as Huntington disease. Structure activity relationship studies yield molecule with greater potency and better CNS penetration potential. Structure activity relationship studies yield molecule with greater potency and better CNS penetration potential. Pharmacokinetic evaluation of one of them is in progress